chr7-6005918-C-T

Variant names:

• chr7-6005918-C-T
• rs121434629
• NM_000535.7:c.137G>A
• PMS2 p.Ser46Asn

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+12 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS3PM2PP3_ModeratePP5_Strong

The NM_000535.7(PMS2):c.137G>A (p.Ser46Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.00000072, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.54). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000552059: Experimental studies have shown that this missense change affects PMS2 function (PMID:24027009)." and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S46G: Uncertain_significance (ClinVar VariationId 525851, 1 star); p.S46R: Uncertain_significance (ClinVar VariationId 1771527, 1 star); p.S46= (synonymous): Likely_benign (ClinVar VariationId 1771525, 1 star) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PMS2 NM_000535.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.54
• Publications: 60 publications found

Genes affected

PMS2 (HGNC:9122): (PMS1 homolog 2, mismatch repair system component) The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

PMS2 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Lynch syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• mismatch repair cancer syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• ovarian cancer

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACMG Germline Pathogenicity v2019

Specifications for PMS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000552059: Experimental studies have shown that this missense change affects PMS2 function (PMID: 24027009).; SCV002013800: Published functional studies demonstrate a damaging effect: deficient mismatch repair activity (PMID: 24027009); SCV001351217: A functional study has shown that this variant protein causes significantly decreased mismatch repair activity in an in vitro assay (PMID: 24027009).; SCV002699807: "In an in vitro study, this alteration displayed less than 10% relative repair efficiency compared to the wild-type control, a level similar to the repair-deficient control (Drost M et al. Hum. Mutat. 2013 Nov; 34(11):1477-80)."; SCV004187643: Functional studies indicate this variant impacts protein function [PMID: 24027009].
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000072 — very rare for AD+AR gene (base 0.0001, raised to 0.000336 by highest known P/LP ClinVar AF 0.000336) — PM2 moderate.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000535.7. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 NM_000535.7	MANE Select	c.137G>A p.Ser46Asn	missense	Exon 2 of 15	Prot: NP_000526.2 UniProt:
	PMS2 NM_001406866.1		c.323G>A p.Ser108Asn	missense	Exon 3 of 16	Prot: NP_001393795.1 UniProt:
	PMS2 NM_001322014.2		c.137G>A p.Ser46Asn	missense	Exon 2 of 15	Prot: NP_001308943.1 UniProt:

PMS2 NM_000535.7

MANE Select

HGVSc / HGVSpc.137G>Ap.Ser46Asn

Exon rankExon 2 of 15

missense

Prot: NP_000526.2UniProt: P54278-1

PMS2 NM_001406866.1

HGVSc / HGVSpc.323G>Ap.Ser108Asn

Exon rankExon 3 of 16

missense

Prot: NP_001393795.1UniProt: A0A8V8TNX6

PMS2 NM_001322014.2

HGVSc / HGVSpc.137G>Ap.Ser46Asn

Exon rankExon 2 of 15

missense

Prot: NP_001308943.1UniProt: A0A8V8TQ50

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	PMS2 ENST00000265849.12	TSL:1MANE Select	c.137G>A p.Ser46Asn	missense	Exon 2 of 15	Prot: ENSP00000265849.7 UniProt:
	PMS2 ENST00000382321.5	TSL:1	c.137G>A p.Ser46Asn	missense	Exon 2 of 11	Prot: ENSP00000371758.4 UniProt:
	PMS2 ENST00000406569.8	TSL:1	n.137G>A	non_coding_transcript_exon	Exon 2 of 13	Prot: ENSP00000514464.1 UniProt:

PMS2 ENST00000265849.12

TSL:1MANE Select

HGVSc / HGVSpc.137G>Ap.Ser46Asn

Exon rankExon 2 of 15

missense

Prot: ENSP00000265849.7UniProt: P54278-1

PMS2 ENST00000382321.5

TSL:1

HGVSc / HGVSpc.137G>Ap.Ser46Asn

Exon rankExon 2 of 11

missense

Prot: ENSP00000371758.4UniProt: P54278-2

PMS2 ENST00000406569.8

TSL:1

HGVSc / HGVSpn.137G>A

Exon rankExon 2 of 13

non_coding_transcript_exon

Prot: ENSP00000514464.1UniProt: P54278-3

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.00000814	AC:2	Hom:	AN:245780	Cov:
GnomAD4 exome Warning	AF: 0.00000206	AC:3	Hom:0	AN:1458548	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Hereditary nonpolyposis colorectal neoplasms (1)
1	-	-	Lynch syndrome 4 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	1.0
GPN-Star LLR	N/A	-5.8
GPN-Star score	N/A	5.8
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.81	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Pathogenic	4.3	H
PhyloP100	Pathogenic	7.5
popEVE	Benign	-4.1
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Varity_R	N/A	0.96
VESM-3B	Benign	-15

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs121434629;

hg19: chr7-6045549;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar